DE69822859T2 - CRYSTALLINE FUNGICIDE POLYMORPH - Google Patents

Description

BACKGROUND OF THE INVENTION

wiedergegeben wird (nachfolgend "die Verbindung der Formel I"), pharmazeutische Zusammensetzungen, die dieses Polymorph enthalten, und Verfahren zur Verwendung dieses Polymorphs zur Behandlung von Pilzinfektionen bei Säugern.This invention relates to the most stable crystalline polymorphic form of I (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1, 2,4-triazol-1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) - hydroxypropyl] -3H-1,2,4-triazol-3-one, represented by Formula I

(hereinafter "the compound of Formula I"), pharmaceutical compositions containing this polymorph, and methods of using this polymorph to treat fungal infections in mammals.

The international publications with the numbers WO 95/17407 (published on June 29, 1995) and WO 96/38443 (published on December 5, 1996) disclose process for the preparation of the compound of formula I. and use thereof for the treatment of fungal infections Mammals. These international patent publications do not disclose or refer to the possible existence of a crystalline one Polymorphs of the compound of formula 1 and do not suggest this yet once before; the synthetic methods disclosed there produce the Compound of formula I as an amorphous solid. In similar Way, WO 96/33178 does not disclose methods of making the crystalline polymorphic form I of the compound of formula I.

to Preparation of pharmaceutical compositions containing the compound of formula I for administration to mammals in accordance with existing regulations the health authority the US and international health authorities, eg. B. Good Manufacturing Practices ("GMP") Requirements of FDA, it is necessary, the compound of formula I in so pure Shape as possible produce, in particular as a form with constant physical Properties.

SUMMARY THE INVENTION

We have found that the compound of formula I in the form of three crystalline polymorphs can exist, each in their own Physicochemical data, their physical properties and differ from one another in their production process and differ from distinguish the amorphous form. These three new crystalline polymorphs Forms described in this specification will be described below designated Form I, Form II and Form III. Of these three forms Form I is the most stable.

wiedergegeben wird und durch das folgende Pulverröntgenbeugungsspektrum gekennzeichnet ist, ausgedrückt in Form von "d"-Abständen und relativen Intensitäten ("RI"):Thus, this invention provides a crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1, 2,4-triazol-1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) - hydroxypropyl] -3H-1,2,4-triazol-3-one, represented by Formula I

and characterized by the following powder X-ray diffraction spectrum, expressed in terms of "d" spacings and relative intensities ("RI"):

These The invention also provides a crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2 , 4-triazol-1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl ] -3H-1,2,4-triazol-3-one, by the following powder X-ray diffraction spectrum (Table 1), expressed in terms of "d" spacings and relative intensities ("RI") (s = strong, m = medium, w = weak, v = very d = diffuse, for example vwd = very slightly diffuse):

Table 1

The The invention further provides pharmaceutical compositions which the crystalline polymorph of form I of the compound of formula I. and the use of the crystalline polymorph of the Compound I for the manufacture of a medicament for the treatment and / or Prevention of fungal infections in a mammal.

SHORT DESCRIPTION THE FIGURES

1 shows a characteristic powder X-ray diffraction spectrum of the crystalline polymorph of the form I [vertical axis: intensity (CPS, counts (square root); horizontal axis: two θ (degrees)].

2 shows a characteristic powder X-ray diffraction spectrum of the polymorph of Form II [vertical axis: intensity (CPS, counts (square root); horizontal axis: two θ (degrees)]; X-ray diffraction shows that Form II is partially amorphous.

3 shows a characteristic powder X-ray diffraction spectrum of the crystalline polymorph of Form III [vertical axis: intensity (CPS, counts (square root); horizontal axis: two θ (degrees)].

4 shows a characteristic infrared spectrum of the crystalline polymorph of Form I in a potassium bromide pellet [vertical axis transmission (%); horizontal axis: wavenumber (cm ^-1 )].

5 shows a characteristic infrared spectrum of the crystalline polymorph of Form II in a potassium bromide pellet [vertical axis transmission (%); horizontal axis: wavenumber (cm ^-1 )].

6 shows a characteristic infrared spectrum of the crystalline polymorph of the form III in a potassium bromide compact [vertical axis transmission (%); horizontal axis: wavenumber (cm ^-1 )].

7 Figure 4 shows a characteristic differential scanning calorimetry thermogram of the crystalline polymorph of Form I [measured on a DuPont 2100: thermal analysis under a nitrogen atmosphere; 10 ° C / min scan rate; Single endotherm, onset temperature: about 166 ° C; vertical axis heat flow in cal / s / g; about 166 °, horizontal axis: temperature in degrees Celsius].

8th Figure 4 shows a characteristic differential scanning calorimetry thermogram of the crystalline polymorph of Form II [measured on a DuPont 2100: thermal analysis under a nitrogen atmosphere; 10 ° C / min scan rate; Endotherm, onset temperature: about 26 ° C; Endotherm, onset temperature about 90 ° C; Exotherm, starting temperature about 113 ° C; Endothermic onset temperature about 163 ° C; vertical axis heat flow in cal / s / g; horizontal axis: temperature in degrees Celsius].

9 Fig. 13 shows a characteristic differential scanning calorimetry thermogram of the crystalline polymorph of Form III [measured on a DuPont 2100: thermal analysis under a nitrogen atmosphere; 10 ° C / min scan rate; Endotherm, onset temperature: about 98 ° C; Exotherm, starting temperature about 114 ° C; Endotherm, onset temperature about 168 ° C; vertical axis heat flow in cal / s / g; horizontal axis: temperature in degrees Celsius].

10 shows a characteristic ¹ H-NMR spectrum of the crystalline polymorph of forms I, II and III [measured on a Vvarian XL400 in CDCl ₃ at 400 MHz with TMS as internal standard].

DETAILED DESCRIPTION OF THE INVENTION

The crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one provides one antifungal agent with the following advantages compared with its amorphous form of the prior art: lower content contamination and more consistent product quality, d. H. more consistent physical characteristics including more consistent Color, dissolution speed and easy handling; as well as longer ones Stability.

The three crystalline polymorphic forms of the compound of the formula designated Form I, II and III can be determined by examination of the characteristic X-ray diffraction spectra (see 1 to 3 ), the characteristic infrared spectra (see 4 to 6 ) and differential scanning calorimetry (DSL) thermograms ( 7 to 9 ) are easily distinguished from each other. Form 1, the most stable form, was transformed under normal conditions (15 ° C to 30 ° C and protected from light) or under the following loading conditions
150 ° C for 2 hours
75 ° C for 6 weeks
97% relative humidity at ambient temperature for 2 minutes
75% relative humidity at 40 ° C for 6 weeks
not in any other form.

In the 8th and 9 shown DSC thermograms show that Form II and Form III are thermally converted at temperatures between 100 and 125 ° C in the more stable Form I. The characteristic physicochemical data of the crystalline polymorph Form I of the compound of formula I are summarized in the following table.

Table Characteristic Physicochemical Data of the Crystalline Polymorphic Form I of the Formula I Compound

All These advantages of the crystalline polymorphic invention Form I of the compound are intrinsic to development and approval a pharmaceutical product useful in the antifungal Active ingredient of the formula I contains.

The crystalline polymorphic form of the compound of Form I can be formed by dissolving the compound of formula I (as free base) using a solvent system such as acetonitrile, methanol in combination with water in a V / V ratio of 1.5: 1 to 1: 1.5, preferably about 1: 1, and isopropyl alcohol in combination with water in a volume / volume (V / V) ratio of 1.5: 1 to 1: 1.5, preferably about 1: 1 crystallized becomes. The solvent or solvent system is typically heated to reflux and slowly cooled to 60-40 ° C with agitation and then slowly to room temperature (20 ° to 25 ° C) or even 0 ° (with acetonitrile), stirring continuously for 1/2 cooled down to 1 hour. The crystalline polymorphic form of the compound of Form II can be formed by dissolving the compound of formula I (as the free base) using a solvent system such as acetone-water in a volume / volume (V / V) ratio of 1.5: 1 to 1: 1.5, preferably about 1: 1, or methylene chloride is crystallized. The product of form III obtained from methylene chloride also contains some amorphous form. The solvent or solvent system is typically heated to reflux and slowly cooled to room temperature (20 ° to 25 ° C) without agitation. The crystalline polymorphic form of the compound of the form III can be formed by adding the compound of formula I (as free base) to a solvent system such as boiling methanol and allowing the resulting solution to cool to room temperature without agitation.

The Infrared spectrum of the crystalline polymorph of Form I, which with a potassium bromide pellet of the crystalline polymorph was, shows the following peaks:

The full Infrared spectrum of the crystalline polymorph of Form II, which with a potassium bromide pellet of the crystalline polymorph was, shows the following peaks:

The full Infrared spectrum of the crystalline polymorph of Form III, which with a potassium bromide pellet of the crystalline polymorph was, shows the following peaks:

The Infrared spectrum was measured on a Mattson Galaxy 6021 FTIR spectrometer receive. The potassium bromide pellets were prepared according to the USP method <197K>, U.S. Pat. Pharmacopeia, National Formulary, USP XXIII, NF XVIII.

The X-ray powder diffraction spectra were on an automated diffractometer system Philips APD3720 (Model PW 1800) measured. The radiation source was copper (K-α), and the long fine focus tube was connected to a Philips XRG 3100 X-ray generator connected with 45 KV and 40 mA. The beam angle was 6 degrees, and a graphite monochromator was used. A scintillation detector was used and the data was with a scan rate of 0.025 degrees per second, a step size of 0.010 and a step time of 40 seconds per degree.

The Powder X-ray diffraction, that of the polymorphic form 1 of descarbonylethoxyloratidine is given in terms of the following characteristic "d" distances and relative intensities ("RI"), below shown:

One more complex powder X-ray diffraction spectrum for the crystalline polymorph of the compound of the formula I, expressed in terms of form the "d" distances and relative intensities ("RI"), where V, M, W, V and D as defined hereinbefore are shown in Table below 1 shows:

Table 1

The crystalline polymorph Form II of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one is by the following powder X-ray diffraction spectrum characterized in the form of "d" spacing and relative intensities ("RI") is indicated:

The crystalline polymorph Form II of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one is by the following powder X-ray diffraction spectrum, expressed in the form of "d" intervals and relative intensities ("RI") (s = strong, m = medium, w = weak, v = very, d = diffuse and vwd, for example = very slightly diffuse), characterized:

The crystalline polymorph Form III of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one is by the following powder X-ray diffraction spectrum, expressed in the form of "d" intervals and relative intensities ("RI"):

The crystalline polymorph Form III of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one is by the following powder X-ray diffraction spectrum, expressed in the form of "d" intervals and relative intensities ("RI") (s = strong, m = medium, w = weak, v = very, d = diffuse and vwd, for example = very slightly diffuse), characterized:

PHARMACEUTICAL COMPOSITIONS

Inventive pharmaceutical Compositions can additionally to an antifungal effective amount of the crystalline polymorph of the compound of formula I as an active ingredient, pharmaceutically acceptable carriers which may be solids or liquids. compositions close in solid form Powders, tablets, dispersible granules, capsules, cachets and suppository one. A solid carrier may be one or more substances, also known as diluents, Flavoring agents, solubilizers, lubricants, suspending agents, Binder or tablet disintegrants can act; It can also be an encapsulant be. In powders is the carrier a finely divided solid which is mixed with the finely divided active Connection exists. In the tablet becomes the active compound with carrier with the necessary binding properties in suitable proportions mixed and becomes the desired Compacted shape and size. The powders and tablets preferably contain about 5 to about 20% of the active ingredient. Suitable solid carriers are magnesium carbonate, Magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, Tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting Wax, cocoa butter and the like. The term "compositions" is intended to include the formulation of the active compound with encapsulating material as a carrier lock in, whereby a capsule is delivered, in which the active component (with or without other carriers) from a carrier surrounded, which is therefore associated with it. Similarly, cachets locked in. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration are.

to Production of suppositories First, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melted and the active ingredient becomes in it homogeneously dispersed as by stirring. The molten homogeneous mixture is then suitably sized Molds poured, cool left and frozen by it.

preparations in liquid Close the mold Solutions, Suspensions and emulsions. As an example, water or water-propylene glycol solutions for the topical Administration can be called. liquid Preparations can also in solution in water Polyethylene glycol solution be formulated. Aqueous solutions, the suitable for which are oral use be prepared by adding the active component to water and suitable dyes, flavorings, stabilizers, sweeteners, Solubilizing and thickening agents are added as needed. aqueous Suspensions suitable for oral use can be prepared Be prepared by adding the finely divided active component in water with viscous Material, d. H. natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

It Also, topical formulation is suitable for nasal or ophthalmic Administration is suitable. A typical formulations for the nasal Administration is suitable solutions or suspensions. Ophthalmic formulations can be solutions, Be suspensions or ointments. Ointments usually contain lipophilic carriers, such as mineral oil and / or Vaseline. solution for the Opthalmic administration may include sodium chloride, acid and / or Base for adjusting the pH and purified water and preservative normally non-toxic, pharmaceutically acceptable, topical carrier is included and she can daily be applied to the affected skin until the condition has improved.

The Antifungal effective amount of the crystalline polymorph of the compound of Formula I for topical administration varies from 0.1 to 20 % By weight of the total pharmaceutical composition normally one or more non-toxic, pharmaceutically acceptable, topical carrier contains; the pharmaceutical composition can be applied daily to the affected area of the skin until the fungal infection has improved. The preferred Amount varies from 0.5 to 10% by weight of the total pharmaceutical Composition.

The Antifungal effective amount of the crystalline polymorph of the compound of formula I for oral administration varies from about 1 to 30 mg / day, especially about 1 to 20 mg / day and most preferred about 1 to 10 mg / day in a single dose or divided doses.

parenteral Forms for intravenous, intramuscular or subcutaneous injection are usually in the form of a sterile solution before and can Containing salts or glucose to make the solution isotonic.

The Parenteral dose in humans for the antifungal use is generally about 25 mg per kg body weight per day to about 20 mg per kg of body weight per day, which is preferred.

The exact amount, frequency and the exact period of administration the compound of the invention for the Of course, antifungal use varies depending on of the sex, the age and the medical condition of the Patients, as well as the severity of fungal infection, as by the responsible Doctor is determined.

GENERAL EXPERIMENTAL PART

The Compounds of the invention be according to the following Examples using commercially available starting materials produced.

There is no crystalline form in solution, and thus the physicochemical characteristics in solution, ie ¹ H-NMR spectra, ultraviolet spectra and specific rotation of the crystalline polymorph and the amorphous forms of the compound of formula I are the same. This in 10 ¹ H-NMR shown is consistent with the structure of the compound of formula I. The specific rotation, measured with the D-line of sodium at 25 ° C, is -29.4.

EXAMPLE 1

Preparation of the crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole) 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

164 g of the example 32 of the International Patent Publication No. WO 95/17407, published June 29, 1995, crude product prepared were in boiling methanol (1.64 L) solved. The hot one solution was filtered through a celite pad and back to reflux heated. To the solution Water (984 ml) was added while the reflux temperature was held. The solution slowed to about 45 ° C cooling down calmly. The resulting mixture was left to stand for one hour Temperature is moved, then slowly cooled to room temperature and continued for an hour. The forming solids were through Collected and filtered with cooled methanol-water (1: 1, about 524 ml). The product was then placed in an oven (45 ° C, 29 psi vacuum, 24 h) to give 156.5 g of white crystals.

EXAMPLE 2

Preparation of the crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole) 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

Two (2) g of the example 1 prepared starting material were in under reflux dissolved isopropyl alcohol (20 ml). Became the solution Add water (20 ml) while at reflux temperature was held. The solution slowed to about 63 ° C cooling down left as the crystallization took place. The resulting mixture was stirred at this temperature for 10 minutes, then slowly to room temperature chilled and continued for an hour. The forming solids were collected by filtration. The product was then placed in an airflow oven (45 ° C, 24 Hours) to give a white solid.

EXAMPLE 3

Preparation of the crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole) 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

Five (5) g of the example 1 prepared starting material were in under reflux dissolved acetonitrile (100 ml). The solution was slow to about Allowed to cool to 50 ° C, when the crystallization occurred. The resulting mixture was 30 minutes at this temperature, then slowly cooled to 0 ° C and moved another 30 minutes. The forming solids were collected by filtration and washed with cooled acetonitrile (25 ml). The product was then placed in an oven (45 ° C, 29 psi vacuum, 12 hours). dried to 3.9 g white To give crystals.

EXAMPLE 4

Preparation of the crystalline polymorphic form II of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole] 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

About 1 g of raw garbage, which was prepared as described above in Example 1 was in under backflow dissolved tenem acetone (10 ml). To this mixture was added water (3 ml) while stirring at reflux temperature was held. The resulting yellow solution became without moving to room temperature cooling down calmly. The resulting solids were filtered off and washed with acetone-water (1: 1, about 5 ml). The product was then placed in an oven (45 ° C, 29 psi vacuum, 24 hours). dried to 0.63 g white To give crystals.

EXAMPLE 5

Preparation of the crystalline polymorphic form II of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole] 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

About 1 g of raw garbage, which was prepared as described in Example 1, was dissolved in 5 ml hot Dissolved methylene chloride and let it dry slowly in a hood. Material of the form II was obtained together with some amorphous material.

EXAMPLE 6

Preparation of the crystalline polymorphic form III of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole] 1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H-1 , 2,4-triazol-3-one

About 2 g raw garbage, prepared as described in Example 1 was dissolved in 10 ml of hot methanol solved. The resulting solution was allowed to cool to room temperature in a hood without agitation. The solids formed were collected by filtration and dried in the hood.

Claims (5)

Crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one, represented by formula I

and characterized by the following powder X-ray diffraction spectrum, expressed in terms of "d" spacings and relative intensities ("RI"):

Crystalline polymorphic form I of (-) - 4- [4- [4- [4 - [[2R-cis) -5- (2,4-difluorophenyl) tetrahydro-5- (1H-1,2,4-triazole -1-ylmethyl) furan-3-yl] methoxy] phenyl] -1-piperazinyl] phenyl-2,4-dihydro-2 - [(S) -1-ethyl-2 (S) -hydroxypropyl] -3H- 1,2,4-triazol-3-one according to claim 1, characterized by the following powder X-ray diffraction spectrum, expressed (Table 1) in the form of "d" intervals and relative intensities ("RI") (s = strong, m = medium , w = weak, v = very weak and d = diffuse): Table 1

Crystalline polymorphic form I according to claim 1 or 2, further characterized by an infrared spectrum obtained with a potassium bromide pellet of the crystalline polymorph and showing the following peaks:

Pharmaceutical composition containing an antifungal effective amount of the crystalline polymorphic form I according to claim 1, 2 or 3 and a pharmaceutically acceptable carrier. Use of the crystalline polymorphic form I according to claim 1, 2 or 3 for the manufacture of a medicament for the treatment and / or Prevention of fungal infections in a mammal.